CH630635A5 - METHOD FOR PRODUCING NEW CEPHALOSPORINE DERIVATIVES. - Google Patents

Description

The invention relates to processes for the preparation of new cephalosporin derivatives with a new acyl radical in the 7-position, which have the formula:

r2nh-

n-

1

n.

-conh-

och

-ti-

^ ch2r5

cooh

(v)

where R.5 represents a hydroxyl or mercapto group or a heterocycle bonded via a sulfur atom and R2NH represents an optionally protected amino group, in particular 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] cephalosporin derivatives, as well as pharmaceutically acceptable salts and esters of these derivatives.

So far, the studies on synthetic cephalosporin derivatives on the conversion of 7-amino-cephalosporanic acid into various acyl derivatives on the 7-

Position or in derivatives directed at the 3-position with the aim of synthesizing compounds with a broad antibacterial spectrum or specific antibacterial spectrum. However, the known cephalosporin derivatives are unsatisfactory in their antibacterial activity against a wide variety of microorganisms.

Cephalosporin derivatives of the formula:

R1's R8 '

yy n u ci chconh

R

(I)

wherein R1 'is an optionally protected amino or hydroxyl group, R2' is an amino group or hydroxyl group or a group which can be converted into these groups, R3 'is hydrogen or a methoxy radical or a group which is convertible to a methoxy radical, R4' is hydrogen or a radical of a nucleophilic compound and R8 'Is hydrogen or a halogen atom, and developed pharmaceutically acceptable salts and esters of these derivatives (DT-OS 25 56 736). The applicant has also found that of these compounds, the compounds of the formula V are extremely active against a broad spectrum of gram-positive and gram-negative bacteria, including Serratia marcescens and Proteus morganii, and that the compounds V are also active against bacteria which Form lactamase, are effective. The invention is based on these findings.

In the compounds of formula V, Rs can in particular be a heterocycle bonded via S (sulfur atom), i.e.

a heterocyclic thio group of the formula -S-heterocycle

50

55

60

65

be. The aforementioned heterocyclic ring is preferably a 5- or 6-membered ring with 1 to 4 hetero atoms from the group consisting of oxygen, sulfur and nitrogen atoms. The nitrogen atom or atoms can be in oxide form. It follows that the heterocyclic group mentioned (ie the group derived from the compound corresponding to the heterocycle) can usually be one of the following groups or another group: pyridyl, N-oxidopyridyl, pyrimidyl, pyridazinyl, N-oxidopyridazinyl, pyrazolyl, di- azolyl, e.g. Pyrazolyl and imidazolyl, thiazolyl, e.g. 1,2-thi-azolyl and 1,3-thiazolyl, thiadiazolyl, e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl and 1,2,5-thia-diazolyl, oxadiazolyl, e.g. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl, triazolyl, e.g. 1,2,3-triazolyl and 1,2,4-triazolyl and tetrazolyl, e.g. 1 H-tetrazolyl and 2H-tetrazolyl. This hetero group can each contain substituents, e.g. lower alkyl radicals with 1 to 3 carbon atoms (e.g. methyl, ethyl and isopropyl), allyl,

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lower alkoxy residues with 1 to 3 carbon atoms (e.g. methoxy, ethoxy and propoxy), halogen atoms (e.g. chlorine and bromine), alkyl residues trisubstituted with halogen atoms (e.g. trifluoromethyl and trichloroethyl), hydroxyl groups, mercapto groups, amino groups, carboxyl groups, carbamoyl groups, Di-lower alkyl (1-3 C-atoms) amino-lower alkyl (1-3 C-atoms) compounds, e.g. Dimethylamino-ethyl and dimethylaminomethyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl and methoxy-carbonylamino.

The number of these substituents that may be present on the heterocyclic group is usually in the range of 1 to 2.

In the compounds of formula V, Rs preferably denotes a heterocyclic thio group, the heterocyclic group of which is unsubstituted or substituted. Preferred substituents of the heterocycle of the heterocyclic thio group are 1 or 2 of the following radicals: lower alkyl radicals having 1 to 4 carbon atoms, di (lower alkyl (Ci-C4) amino-substituted lower alkyl (C1-C4), carboxymethyl, amino, methoxycarbonylamino , Carbamoylmethyl, carboxymethylthio and sulfomethyl The preferred radical Rs are 1-methyl-1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1,2-dimethyl-1,3 , 4-triazol-5-ylthio etc.

The R2NH group is an amino group that can optionally be protected. R2 is therefore a hydrogen atom or a protective group for the amino function, any known protective groups generally used for the protection of amino groups, i.e. usual protecting groups for the amino function come into question. Aromatic acyl residues, e.g. Phthaloyl, benzoyl, benzoyl groups substituted with halogen atoms, nitro groups or lower alkyl radicals with 1-4 C atoms (e.g. chlorobenzoyl, p-nitrobenzoyl, pt-butylbenzoyl and toluoyl) and naphthoyl, phenylacetyl, phenoxyacetyl, benzenesulfonyl radical benzenesulfonyl groups substituted with 1 to 4 carbon atoms (for example pt-butylbenzenesulfonyl and toluenesulfonyl), acyl radicals derived from aliphatic or halogenated aliphatic carboxylic acids, for example Acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl and haloacetyl (e.g. monochloroacetyl, monobromacetyl, dichloroacetyl and trichloroacetyl), camphor sulfonyl, methanesulfonyl, esterified carboxyl groups, e.g. Ethoxycarbonyl, t-butyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl and benzyloxycarbonyl, carbamoyl groups, e.g. Methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl and the corresponding thiocarbamoyl groups.

The cephalosporin derivatives of formula V can take the tautomeric form, i.e. fertilize as 2-aminothiazole-Verbin-25 and 2-iminothiazoline compounds, which are shown below, but they are described here as thiazole compounds.

15

20th

ÎL 1CH2R5 cooh

R2N

-! J-c-conh h ii n.

N-

xoch, 0 '

cooh c h_fl

2 D

The carboxyl group in the 4-position of the compound of formula V can be free, but can also form a salt with a non-toxic cation, e.g. an alkali salt, e.g. a sodium or potassium salt, a basic amino acid, e.g. Arginine, ornithine, lysine or histidine, or a polyhydroxyalkylamine, e.g. N-methylglucamine, diethanolamine, triethanolamine or trishydroxymethylaminomethane. Compounds V can be salts with inorganic acids such as hydrochloric acid and sulfuric acid or with organic acids, e.g. Toluenesulfonic acid and benzenesulfonic acid. The 4-carboxyl group can also be in the form of a biologically active ester, which has the advantage, for example, of an increase in the concentration in the blood and long-lasting effectiveness. Examples of such ester residues are:

Lower alkoxymethyl residues, e.g. Methoxymethyl, ethoxy-methyl, isopropoxymethyl, a-methoxyethyl and a-ethoxy-ethyl, a-lower alkoxy-a-substituted methyl groups such as e.g. a-lower alkoxy (Ci-C4) ethyl, e.g. Methoxymethyl, ethoxyethyl, propoxyethyl and isopropoxyethyl, lower alkylthiomethyl radicals with 1-3 C atoms, e.g. Methylthio-methyl, ethylthiomethyl and isopropylthiomethyl, acyloxy-

50

methyl residues, e.g. Pivaloyloxymethyl and a-acetoxymethyl, ethoxycarbonyloxy-l-methylmethyl and a-acyloxy-a-substituted methyl residues (e.g. acetoxy-a-methylmethyl). The preparation of these salts and esters also falls within the scope of the invention.

Like the known cephalosporins or penicillins, the compounds V can be administered in the form of medicaments, such as injection solutions, capsules, tablets and granules. The compounds V are thus new compounds which show excellent activity against a broad spectrum of bacteria, including gram-negative bacteria, such as Escherichia coli, Serratia marcescens, Proteus rett-geri, Enterobacter cloacae and Citrobacter freundii and are resistant to β-lactamase are. The compounds V can be used, for example, as disinfectants for removing the above-mentioned microorganisms from surgical instruments or as agents for combating infections. When used as an agent to treat infections e.g. for the treatment of peritoneum infections, infections of the respiratory tract, urinary tract and other infectious diseases caused by the above-mentioned microorganisms, they can warm-blooded animals including humans,

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65

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Mice and rats can be safely administered in a daily dose of 0.5 to 80 mg, preferably 1 to 20 mg / kg body weight in 3 to 4 daily doses. The compounds V can be administered orally or parenterally in various pharmaceutical forms, such as injection solutions, capsules, powders, granules and tablets, which can be prepared by known processes. When using the compounds V for injections, for example, distilled water or physiological saline can be used as the carrier. When used in capsules, powder, granules or tablets, the compound V beir2nh.

f i |

n ll

10th

c conh for example in a mixture with pharmacologically harmless, known auxiliary substances (e.g. starch, lactose, sucrose, calcium carbonate and calcium phosphate), binders (e.g. starch, gum arabic, carboxymethylcelulose, hydroxypropyl cellulose and crystalline cellulose), lubricants (e.g. magnesium stearate and talc) and disintegrants (e.g. carboxymethyl calcium and talc) are used.

According to the invention, the compounds of the formula V are prepared by reacting compounds of the formula:

och

—Ri

^ ch2r4

cooh

(iv)

wherein R2NH has the meaning given above and R4 stands for acyloxy, carbamoyloxy or halogen, with a compound of the formula HRs and, if appropriate, subsequent removal of the protective group for the amino group.

As an acyloxy radical for which R4 in formula IV stands,

Examples include: acyloxy radicals derived from lower aliphatic carboxylic acids with 2 to 4 carbon atoms, which may optionally be substituted with oxo groups, carboxyl groups or 30 ethoxycarbamoyl groups, e.g. Ace-tyloxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyloxy, 3-ethoxycarbamoylpropionyloxy and 4-carboxybu-tyryloxy, and acyloxy radicals derived from aromatic carboxylic acids, which may be substituted with hydroxyl groups, Car- 35 boxyl groups, carboethoxy carbamoylamoylamoylamoylamoylamoylamoyl can, e.g. Man-delyloxy, 2-carboxybenzoyloxy, 2- (carboethoxycarbamoyl) benzoyloxy and 2- (carboethoxysulfamoyl) benzoyloxy. The halogen atom for which R4 stands is, for example, chlorine, bromine and iodine. However, it is generally convenient to use a compound IV which contains an acyloxy radical derived from a lower aliphatic carboxylic acid, e.g. Acetyloxy. 45

Particularly preferred compounds HR5 are heterocyclic thiol compounds, i.e. such mercapto compounds. The mercapto compounds can be used in their free form, but it is advantageous to use them in the form of alkali salts, e.g. Sodium or potassium salts to use. This reaction is preferably carried out in a solvent. Examples of solvents are water, deuterium or an organic solvent which is readily miscible with water and does not react with the reactants, e.g. Dimethylform 55 amide, dimethylacetamide, dioxane, acetone, alcohol, acestonitrile, dimethyl sulfoxide and tetrahydrofuran, are used. The reaction temperature and the reaction time change with factors such as the respective starting material and the solvent used, but the temperature is generally between 0 and 100 ° C, preferably between about 30 and 70 ° C, and the reaction time is generally between 2 and 48 Hours, preferably between about 3 and 15 hours. The reaction is preferably carried out in the vicinity of the neutral point, suitably at a pH in the range from about 2 to 8, preferably 5 to 8. This reaction can sometimes be carried out by adding a quaternary ammonium salt with surface activity, e.g. Trimethylbenzylammoniumbromid or Triäthyl-benzylammoniumbromid or Triäthylbenzylammoniumhydroxyd, be made smooth. Furthermore, better results are obtained when the reaction is carried out in an inert gas atmosphere, e.g. Nitrogen is carried out to prevent oxidation of the mercapto compound by atmospheric oxygen.

After the reaction, the protecting group of the amino function can be removed if desired. The protective group can generally be removed by methods known per se (for example by the method described in Japanese Patent Application Laid-Open 52083/1975 and in Pure and Applied Chemistry, 7 (1963), 335) or a method analogous to this method.

The protecting group R2 for the amino group is preferably a monohaloacetyl group. The reaction for removing the monohaloacetyl group from the amino group is carried out by reacting the compound of formula V whose amino group has been protected with a monohalogenoacetyl group with thiourea and a basic substance. Usually this reaction is carried out in a solvent at a temperature near room temperature. In many cases, the reaction takes 1 to 10 hours or more to complete. Any solvents that do not interfere with the reaction can be used. For example, ether, e.g. Ethyl ether, tetrahydrofuran and dioxane, lower alcohols, e.g. Methanol and ethanol, halogenated hydrocarbons e.g. Chloroform and methylene dichloride, esters, e.g. Ethyl acetate and butyl acetate, ketones, e.g. Acetone and methyl ethyl ketone, water and various mixtures of these solvents.

Suitable basic substances are, for example, alkali or alkaline earth metal salts of lower aliphatic carboxylic acids or inorganic or organic bases with a pKa value of not less than 9.5, preferably in the range from 9.8 to 12.0. Examples of suitable salts of lower aliphatic carboxylic acids are the salts of lower aliphatic carboxylic acids with 1 to 6 carbon atoms, e.g. Sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate and potassium hexanoate. As examples of suitable inorganic bases are the alkali salts of carbonic acid, e.g. Sodium carbonate and potassium carbonate. Suitable organic bases are, for example, simple with lower alkyl radicals,

doubly or triply substituted amines having 1 to 4 carbon atoms in the alkyl radical, e.g. Trimethylamine, triethylamine,

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Ethylamine, methylamine, diethylamine, dimethylamine, tri-butylamine, dibutylamine and butylamine, and 5- to 6-membered cyclic amines which are substituted in the N-position with lower alkyl radicals having 1 to 2 carbon atoms, e.g. N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine and N-ethylpiperazine. As mentioned above, thiourea is used in this reaction, but the reaction can also be successful with N- or N, N-substituted thio-ureas, e.g. Methylthiourea, N, N-diethylthio-urea or N, N-hexamethylene thiourea can be carried out.

The cephalosporin compounds V prepared by the various processes described above can be prepared by processes known per se, e.g. by column chromatography, extraction, precipitation and recrystallization. If necessary, each of these compounds can be converted into the desired salts, esters, etc. by methods known per se.

One of the starting materials for the compounds according to the invention, the cephalosporin derivative of the formula 20 IV, can be prepared by acylating the 7-amino group of a 7-aminocephalosporin compound of the formula:

10th

15

• 25th

ch2e,

(II)

cooh in which R4 has the meaning given above, with a 2- (2-

Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid

Formula:

or a suitable condensing agent is used in the form of a salt. Suitable condensing agents are, for example, N, N'-disubstituted carbodiimides, e.g. N, N'-dicyclohexylcarbodiimide, azolides, e.g. N, N'-carbonylimidazole and N, N'-thionyldiimidazole, dehydrating agents, e.g. N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene, 2-halopyridinium salts (e.g. 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide). It is believed that when such a condensing agent is used, the reaction proceeds via the reactive derivative of carboxylic acid III. The reaction is generally carried out in an inert solvent. Examples of suitable solvents are: halogenated hydrocarbons, e.g. Chloroform and methylene dichloride, ether, e.g. Tetrahydrofuran and dioxane, dimethylformamide, dimethyl acetamide, acetone, water and mixtures of these solvents. The proportion of the acylating agent is normally in the range from about 1 to 5, preferably 1 to 2 molar equivalents, based on the compound II. This reaction is generally carried out at a temperature in the range from -50 ° to + 40 ° C. The reaction time can vary from about 1 to 10 hours, generally from 1 to 3 hours. After the acylation, the protective group of the amino function can, if desired, be removed by known methods, as has already been described above.

The 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid derivative III can be prepared, for example, by various methods, which are described in detail below.

(I) First, a 4-halo-3-oxo-2-oxyiminobutter acid derivative of the formula VII

R2NHTn n u-c-cooh

II

H

^ OCH,

35

(VII)

(III)

wherein R2NH has the meaning given above, if appropriate with subsequent removal of the protective group of the amino group.

In this process, compound III is used either in free form or in the form of a reactive derivative as an acylating agent for the acylation of the amino group in the 7-position of compound II. Free acid III, an alkali or alkaline earth metal salt of free acid III (e.g. the sodium, potassium or calcium salt) becomes an organic amine salt of free acid III (e.g. the trimethylamine salt or pyridine salt) or a reactive derivative of the compound ( for example, an acid halide (for example, the acid chloride or acid bromide), an acid anhydride, a mixed acid anhydride, an active amide or an active ester) are subjected to the above-mentioned acylation reaction. Examples of suitable active esters are the p-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester and the N-hydroxyphthalimide ester. Examples of mixed acid anhydrides are mixed acid anhydrides with a carbonic acid monoester (e.g. carbonate monomethyl ester or carbonic acid mono-isobutyl ester) and mixed acid anhydrides with a lower alkanoic acid, which can be substituted with a halogen atom (e.g. pivalic acid or trichloroacetic acid). When using carboxylic acid III as the free acid

45

XCH2COC-COOR7

ii

N

s

ORô

where X is a halogen atom, e.g. Chlorine or bromine, Ro hydrogen or a methyl radical and R7 is a lower alkyl radical with 1 to 3 C atoms, e.g. Methyl, ethyl or propyl is reacted with thiourea, a 2- (2-aminothiazol-4-yl) -2-oxyiminoacetic acid derivative of the formula VIII

H2N-irsii

SO YY U-C-

G'

11

N?

-COORr

(VIII)

55

60

65

0R6

wherein Rßund R7 have the meanings given above, is obtained. In the two cases in which Rô is hydrogen and methyl, the compound VIÏI is normally obtained as a mixture of syn and anti isomers. The reaction is usually carried out by combining a compound of formula VII with thiourea in an organic solvent, e.g. Ethanol, methanol or tetrahydrofuran, at room temperature or elevated temperature (0 to 100 ° C, preferably 10 to 50 ° C) is reacted. The reaction time is generally 1 to 30 hours, preferably 1 to 5 hours.

To isolate the desired syn isomer from the

7

obtained mixture of the syn and anti forms of compound VIII, one of the following methods can be successfully used:

a) Fractional crystallization, in which the different crystallizabilities or solubilities of the isomers of compound VIII as such, a salt of compound VIII with hydrogen halide (HBr or HCl salt) or a derivative of compound VIII with a known per se Protective group introduced in this way (for example mono- chloroacetyl or dichloroacetyl) on its 2-amino group.

b) isolation by chromatography and c) a process in which the compound VIII or the 15 containing a protective group on its 2-amino group containing compound VIII at its ester position in a manner known per se to hydrolyze to a carboxylic acid derivative of the formula III and the selectively isolating syn isomers solely by taking advantage of the difference in hydrolysis rate between the 20 and anti isomers.

In the latter method, due to the fact that the rate of hydrolysis of the anti isomer is higher than that of the syn isomer, the anti isomer can be selectively hydrolyzed and removed. The reaction for 2s hydrolysis of the ester bond of compound VIII with or without a substituent on its 2-amino group is normally carried out in the presence of 1 to several molar equivalents of an alkali hydroxide, e.g. Potassium hydroxide or sodium hydroxide, at a temperature of 0 ° C to room temperature 30 in water or in a mixture of water with

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a water-miscible organic solvent, e.g. Methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide or N, N-dimethylacetamide. When Ro in compound VIII is hydrogen, the isolated syn isomer can be converted to the syn isomer of compound VIII in which R6 is a methyl radical by methylating the former compound VIII. This methylation reaction is usually carried out in a solvent with ice cooling or at temperatures near room temperature, and in many cases takes from a few minutes to several hours to complete. Any solvent can be used for this purpose, provided that it does not interfere with the reaction. For example, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide and water and mixtures of these solvents are suitable. Examples of suitable methylating agents are methyl halides, e.g. Methyl iodide and methyl bromide, dimethyl sulfate and diazomethane, to name a few. In all cases, except when using diazomethane, compound VIII in which Rô is hydrogen is reacted with the methylating agent in the presence of a base, e.g. an alkali carbonate (e.g. sodium carbonate and potassium carbonate) or an alkali hydroxide (e.g. sodium hydroxide and potassium hydroxide). Some physical constants of the syn isomers of compounds III and VIII prepared in this way are listed in Table 1 below in comparison to the physical constants of the corresponding anti isomers.

Table 1

Structure NMR spectrum (ppm) Melting point, ° C

syn isomer h2n

"St.

Tcr-I-LL

n - • —— c-cooc ^ c ii ^

n.

v oh

In d6-DMSO

6.80s (5-H)

ll, 6s (OH)

185.5

anti-isomer vvs n ll

C-COOCgH ^

n ho

/

In d6-DMSO

7.50s (5-H)

12.5s (OH)

145.3

syn isomer

HoN

2 "-IT Ì)

n - "- c-c00coh, -

ii y n

och-

InCDCb

6.74s (5-H)

4.02s (OCH3)

163 to 164

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8th

Table 1 continued

structure

NMR spectrum (ppm) melting point, ° C

anti-isomeric syn-isomer h2N

~ if i |

N ü — c-

c00cohc lt c-?

n

H2N

CHjO

s. .

"ff ì)

n li c-cooch ^ nn

OCI ^

InCDCb

7.43s (5-H)

4.07S (OCH3)

InCDCb

4.74s (5-H),

4.02S (OCH3)

114 to 115

164.9

anti-isomer h2n n

c-cooch ^ N

ch-, 0 0

/

InCDCb

7.48s (5-H),

4.06s (OCH3)

syn isomer c / ch2conh if I

b - "- c-coocoh, ii 2 5

N

V0CH ^

InCDCb

7.15s (5-H)

4, OOS (OCH3)

111 to 112

anti-isomer

Ö / CHgCONH S> |

m ll n *

n c-cooc-hill 2 5

n

CHjO '

In CDCb

7.94s (5-H)

4.10S (OCH3)

81 to 82

syn isomer

C ^ CHoCONH

2ouinh — ß '||

n — x-cooh '

if

1k och5

In dô-DMSO

7.57s (5-H)

3.95s (OCH3)

170 to 171

syn isomer c / ch ~ conh

1-jl c-cooh il n

CILo '

0

In dô-DMSO

8.00s (5-H)

4, OOS (OCHB)

182 to 183

9

Table l continued

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structure

NMR spectrum (ppm)

Melting point, ° C

c ^ chpccnh—

syn-isomer kT II «

il ••

c00ch-,

InCDCb

7.24s (5-H),

4.02S (OCH3)

130.8

n

'oh.

c / ch2conh anti isomer

~ if ii n —u- c-cooch,

II 5

N

CH-, 0 ^

InCDCb

8.02s (5-H)

4.12s (OCHs)

Comments on Table 1:

s: single

The methoxyimino (hydroxyimino) group in the «syn» isomer is in the cis-stellu carboxyl function.

(II) The process for the selective preparation of compound III (syn isomer) is described below. During the above implementation of the compound

VII with thiourea gives a mixture of syn- and anti-isomers of compound VIII, in many cases the anti-isomer of compound VIII predominates. The investigation of the 35 conditions of this cyclization reaction by the applicant shed light on the conditions of a selective one Formation of the desired syn isomer are beneficial. So when carrying out the reaction of compound VII with thiourea to prepare the compound ^

VIII under the conditions described above, the syn and anti isomers are normally formed in a ratio of 2:98 to 50:50.

However, it has been found that when this cyclization reaction is carried out in water or a mixture of 4S water with a water-miscible solvent such as methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpiperidone and in the presence of a basic substance, the syn isomer of compound VIII is selectively formed s0 (usually in a ratio of about 85:15 to 100: 0). Suitable basic substances for the purposes of this reaction are, for example, alkali or alkaline earth metal salts of lower aliphatic carboxylic acids and inorganic or organic bases with pKa values of not less than 55 9.5, preferably in the range from 9.8 to 12.0. Examples of these salts of lower aliphatic carboxylic acids are the salts of lower aliphatic carboxylic acids with 1 to 6 C atoms, e.g. Sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate 60 and potassium hexanoate, while as the inorganic bases mentioned above, alkaline salts of carbonic acid, e.g. Sodium carbonate and potassium carbonate. Examples of suitable organic bases are: trialkyl-substituted amines with a lower-6s their Ci-C4-alkyl radical, e.g. Trimethylamine, triethylamine and tributylamine, and 5- to 6-membered cyclic amines which are in the N position with a lower alkyl radical having 1 to 2

to the carboxyl function and in the «anti» isomer in the trans position

C atoms are substituted, e.g. N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine and N-ethylpiperazine. When using N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone as a solvent, it is not always necessary to add the above-mentioned basic substance. The temperature is generally kept between 0 and 50 ° C, preferably between about 0 and 30 ° C; the reaction time is generally 1 to 30 hours, preferably 1 to 5 hours.

(III) Compound VIII (syn isomer) can also be selectively prepared by the method described below. In a further search for a process for the selective production of the syn isomer, the applicant found that by reacting a 2-aminothhiazol-4-ylglyoxylic acid derivative of the formula IX with O-methylhydroxylamine, the syn isomer of the methoxyimino compound was selectively prepared can be:

white | ,

n-u-c-coorr; (ix)

Herein R2 and R7 have the meanings given above.

Usually, this reaction can be carried out smoothly in a suitable solvent at a pH of about 4.0 to 9.0. Any solvents that do not interfere with the reaction can be used. For example, ether, e.g. Ethyl ether, tetrahydrofuran and dioxane, lower alcohols, e.g. Methanol and ethanol, halogenated hydrocarbons e.g. Chloroform and methylene dichloride, esters, e.g. Ethyl acetate and butyl acetate, water and mixtures of these solvents. This reaction is near room temperature, but can be accelerated by heating. The temperature is generally kept between 0 and 100 ° C, preferably between about 10 and 50 ° C; the reaction time is generally

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mean 1 to 10 hours, preferably 1 to 5 hours.

The starting compound IX for this reaction can be prepared by the reaction described below. The preparation is carried out by hydrolysis of a nitron compound of the formula X

r2m- | fsi n c-coor9. (x)

\\ f

ü-n-ch,

+?

wherein R2 and R7 have the meanings given above. This hydrolysis reaction takes place smoothly in the presence of a mineral acid and is usually carried out in a solvent. Examples of suitable mineral acids are hydrochloric acid, sulfuric acid and phosphoric acid. Any solvents that do not interfere with the reaction can be used. For example, ether, e.g. Tetrahydrofuran and dioxane, alcohols, e.g. Methanol and ethanol, ketones, e.g. Acetone and methyl ethyl ketone, water and mixtures of these solvents. Usually this reaction is carried out with ice cooling or at room temperature. The starting compound X can be prepared by subjecting a compound of the formula VIII, in which R6 is hydrogen and whose amino group has been protected in the 2-position, to methylation.

The conditions of this methylation reaction are essentially the same as the conditions under which the above compound VIII, in which Ró is hydrogen, is methylated (see Method I described above).

Under the methylation conditions described, the methylation of the syn isomer of compound VIII, in which Ro is hydrogen, does not give a substantial amount of this nitron compound X, but by methylation of the anti isomer of compound VIII, in which R6 is hydrogen, the nitron compound X is predominant Received product.

The compound of formula VII can be, for example, by the methods described in Journal of Médicinal Chemistry, 16 (1973), 978, Helvetica Chimica Acta, 49 (1966) 26, Journal of the American Chemical Society, 60 (1938) 1328 and in DT-OS 25 56 736 described, or be prepared by similar processes. The compound of formula II used for the purposes of the invention can be prepared, for example, by one of the processes described in the following publications: US Pat. Nos. 3,875,151 and 3,697,515, DT-OS 2461478, DT-OS 2607 064 (Dutch patent application 76.01902), DT-OS 2619 243, Japanese published patent application 52083/1975 and DT-OSen 2460 331 and 24 60 332. The preparation can also be carried out by methods which are analogous to the aforementioned methods.

The optionally substituted heterocyclic thiol compound RsSH used according to the invention as a nucleophilic compound, in which Rs has the meaning given above, can be published, for example, according to the processes described in the Journal for Practical Chemistry, NF 133 (1932), Heterocyclic Compounds, 8 by Robert C. Elderfield (John Wiley & Sons) and Advances in Heterocyclic Chemistry, edited by AR Katritaky, A.J. Boulton (Academic Press) can be described, or be prepared by analogous processes.

The compound IV can, for example, according to the

BE-PS 719 710 described processes or a process analogous to this process.

The invention is illustrated in the following examples. In these examples, the abbreviation «DMSO» stands for dimethyl sulfoxide. The resins of the "Amberlite" trade name are products from the Rohm & Haas Company, USA. All temperatures are uncorrected. The percentages are by weight unless otherwise stated. The NMR spectra were recorded with a “Varian Model HA 100” (100 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as an internal or external reference. All S values are given in ppm. Furthermore, s = singlet, d = doublet, t = triplet, q = quartet, m = multiple, and J is a coupling constant.

Reference Example 1

10 g of ethyl 3-oxo-2-hydroxyiminobutyrate are dissolved in a solution of 13.3 g of sodium carbonate in 120 cc of water. 30 ccm of methanol are added to the solution. The mixture is ice-cooled. With stirring, 15.8 g of dimethyl sulfate are added dropwise within 3 minutes. After the addition, the ice bath is removed and the mixture is stirred for 40 minutes at room temperature. The reaction mixture (pH 8 or higher) is extracted twice with ethyl acetate. The extracts are poured together, washed with water and dried. The solvent is then evaporated under reduced pressure. The residue is distilled under reduced pressure.

This gives 9 g of ethyl 3-oxo-2-methoxyiminobutyrate as a pale yellow oil with a boiling point of 56 ° to 61 ° C / 0.3 to 0.4 mmHg.

Elemental analysis for CzH 11NO4

Calculated: C 48.54; H 6.40; N 8.08 Found: C 48.41; H 6.51; N 7.96

NMR spectrum (60 MHz, in CDCls):

2.40 ppm (3H, singlet, CH3CO), 4.10 ppm (3H, singlet,

= STILL3)

Reference Example 2

(1) 27.3 g of ethyl 3-oxo-2-methoxyiminobutyrate are dissolved in 120 cc of chloroform. The solution is heated to 40 ° C. Then a solution of 25.3 g of bromine in 30 cc of chloroform is added dropwise in 30 minutes. The mixture is stirred and left to react at room temperature for 1 hour. The reaction mixture is washed with 5% aqueous sodium hydrogen carbonate solution and water in this order. The organic layer is dried. The solvent is distilled off under reduced pressure, whereby 36.2 g of ethyl 4-bromo-3-oxo-2-methoxyimiriobutyrate are obtained as an oily product.

NMR spectrum (60 MHz, in CDCh):

4.16 ppm (3H, singlet, OCH3), 4.36 ppm (2H, singlet,

BrCmCO)

(2) 5 g of the above product are dissolved in 20 cc of ethanol. 1.8 g of thiourea are added to the solution. The mixture is heated for 3 hours on a reflux condenser. After cooling, the precipitate is filtered off and dissolved in 20 cc of water. Sodium bicarbonate is added to the solution. The separated oil is extracted with ethyl acetate. The ethyl acetate layer is washed and dried. The ethyl acetate is then evaporated off, white crystals being obtained.

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Recrystallization from ethanol gives 2.6 g (57.2%) of ethyl 2- (2-aminothiazol-4-yl) -2- (anti) -methoxyiminoacetate in the form of white crystals with a melting point of 114 ° to 115 ° C. .

Elemental analysis for CsHi 1N3O3S

Calculated: C 41.91; H 4.84; N, 18.33. Found: C, 41.71; H 4.75; N 18.07

NMR spectrum (60 MHz, in CDCb):

4.07 ppm (3H, s, OCH3), 5.80 ppm (2H, br s, NH2), 743 ppm

(1H, s, thiazole5H)

(3) The filtrate obtained after isolation of the first amount of precipitation is concentrated under reduced pressure. Sodium bicarbonate is added to the residue. The mixture is extracted with ethyl acetate. The oil obtained from the ethyl acetate layer is purified by column chromatography on silica gel. 59 mg (1.3%) of ethyl 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate are obtained in the form of white crystals with a melting point of 163 ° to 164 ° C.

Elemental analysis for C8H11N3O3S:

Calculated: C 41.91; H 4.84; N, 18.33. Found: C, 41.57; H 4.76; N 18.07

NMR spectrum (60 MHz, in CDCb):

4.02 ppm (3H, s, OCH3), 5.80 ppm (2H, br s, NH2), 6.74 ppm

(1H, s, thiazole 5H)

Reference Example 3 121 g of ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate are added to 600 cc of ethanol together with 47.6 g of thiourea. The mixture is stirred for 3 hours at room temperature. The ethanol is then evaporated under reduced pressure, after which 350 cc of water are added. The water layer is washed with ether, neutralized with sodium hydrogen carbonate (to pH 7.5) and extracted with ethyl acetate-tetrahydrofuran (1: 1). The organic layer is washed with water and dried. The solvent is then distilled off to give 45 g of a church stall product.

A 1 g sample of this product is taken and purified by column chromatography on silica gel (eluent: ethyl acetate-n-hexane). The first fraction gives 650 mg of the anti-isomer of ethyl 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetate. 150 mg of the syn isomer are obtained from the second fraction.

anti-isomer: white crystals, melting point 145.3 ° C syn-isomer: pale yellowish white crystals, melting point 185.5 ° C

Elemental analysis for C7H9N3O3S:

Calc .: C 39.06; H 4.21; N 19.52 Found:

(anti) C 38.81; H 4.20; N 19.62

(syn-) C 39.28; H 4.10; N 19.63

NMR spectrum (60 MHz, in de-DMSO):

anti-isomer: 7.10 ppm (2H, br s, NH2), 7.50 ppm (1H, s, thiazole 5-H), 12.5 ppm (IH, s, OH)

syn isomer: 6.80 ppm (1H, s, thiazole 5-H), 7.12 ppm (2H, br s, NH2), 11.6 ppm (1 H, s, OH)

Reference Example 4 10.6 g of sodium carbonate are dissolved in 150 cc of water. A solution of 10.7 g of ethyl 2- (2-aminothiazol-4-yl) -2- (syn) -hydroxyiminoacetate in a mixture of 150 cc tetrahydrofuran and 50 cc methanol is added to the solution. While cooling with ice, 12.6 g of dimethyl sulfate are added dropwise in 5 minutes. After the addition, the ice bath is removed and the mixture is stirred at room temperature. White crystals begin to separate while stirring. After 3 hours, most of the organic solvent is distilled off under reduced pressure and the residue is cooled with ice. The precipitate formed is filtered off, washed with water and dried. 5 g of ethyl 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate are obtained in the form of white crystals. Based on the NMR spectrum and other properties, this product is identified as ethyl 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetate.

Reference Example 5 2.15 g of ethyl 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate (melting point 163 ° to 164 ° C.) are dissolved in 10 ccm of N, N-dimethylacetamide while melting with ice is cooled. 1.27 g of chloroacetyl chloride are added dropwise to the solution. The mixture is stirred with ice for 30 minutes and then at room temperature for 30 minutes. The reaction mixture is diluted with 50 cc of water and extracted twice with 100 ccm of ethyl acetate. The extracts are poured together, washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order and then dried. The solvent is then evaporated to give 2.04 g of ethyl 2 ~ (2-chloroacetamfidothiazol-4-yl) -2- (syn) -methoxyiminoacetate as a crystalline product of melting point 111 ° to 112 ° C.

Elemental analysis for C10H12N3O4SCI:

Calculated: C 39.29; H 3.96; N 13.74 Found: C 39.15; H 3.91; N 13.69

NMR spectrum (60 MHz, in CDCb):

4.00 ppm (3H, s, = NOCHs), 4.24 ppm (2H, s, CICH2CO), 7.15 ppm (1H, s, thiazole 5-H)

Reference Example 6 9.62 g of ethyl 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetate are added to a solution of 9 g of potassium hydroxide in a mixture of 85 cc of water and 452 ccm of ethanol. The mixture is stirred for 2 hours at room temperature. The ethanol is distilled off under reduced pressure. After adding 85 cc of water, the residue is washed with 100 cc of ethyl acetate. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and then extracted twice with 200 cc each of ethyl acetate. The extracts are combined, washed with saturated aqueous sodium chloride solution and dried. The solvent is distilled off, giving 7.63 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -me-thoxyiminoacetic acid in the form of crystals of melting point 170 ° to 171 ° C.

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Elemental analysis for C8H8N3O4SCI:

Calc .: C 34.60; H 2.90; N, 15.13. Found: C, 34.97; H 3.03; N 14.74

NMR spectrum (60 MHz, in ck-DMSO):

3.95 ppm (3H, singlet, = NOCH3), 4.40 ppm (2H, singlet,

CICH2CO), 7.57 ppm (1H, singlet, thiazole 5-H)

10th

Reference Example 7 In the manner described in Reference Example 5, 2.38 g of a 7: 8 mixture of the syn and anti isomers of ethyl 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetate is chloroacetylated with chloroacetyl chloride. 30 cc of ether are added to the resulting mixture 15 of the syn and anti forms of ethyl 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetate. The crystals deposited here are filtered off (product (A)). The NMR spectrum and other properties indicate that this product 20 is identical to the ethyl 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) methoxy-iminoacetate prepared according to Reference Example 5. Yield 600 mg.

The oil obtained by concentrating the filtrate (2.42 g,

Mixture of the syn and anti isomers) is added to a solution 2s of 879 mg of potassium hydroxide in a mixture of 5 cc of water and 80 ccm of ethanol, while cooling with ice. The entire mixture is stirred at this temperature for 15 minutes. The ethanol is distilled off under reduced pressure and the residue is diluted with 50 cc of 30 water and extracted twice with 100 ccm of ethyl acetate. The ethyl acetate layer is washed with water and dried. The ethyl acetate is distilled off,

whereby 577 mg of ethyl 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetate (product (B)) are obtained. In the 35 NMR spectrum and in the other properties, this product is identical to the syn isomer prepared according to Reference Example 5. The products (A) and (B) are obtained in a total yield of 1076 g, corresponding to 96.8%.

40

Reference example S 1.5 g of ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate are dissolved in 10 cc of tetrahydrofuran. After adding 7 cc of water, 2.4 g of sodium acetate trihydrate and 0.9 g of thiourea are also added. The mixture is stirred at room temperature for 17 hours for 4s and then concentrated under reduced pressure. The concentrate is adjusted to pH 1.5 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer is neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated under reduced pressure to give 0.8 g of yellowish crystals. This product is ethyl 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetate. On the basis of the NMR spectrum and other key figures, it is determined that this product is identical to the syn isomer prepared according to Reference Example 2.

Reference Example 9 While a mixture of sodium azide, ethanol and 6 »water is heated with stirring on a reflux condenser, an ethanolic solution of N, N-dimethylaminoethyl isothiocyanate is added dropwise. The mixture is refluxed for a further 45 minutes, after which the ethanol is distilled off under reduced pressure. The solution remaining as a residue is acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to dryness. The crystalline residue is stirred with n-hexane, filtered off and recrystallized from toluene. This gives l- (2-N, N-dimethylaminoethyl) -lH-tetrazole-5-thiol with a melting point of 217 ° to 219 ° C (recrystallized from aqueous ethanol).

NMR (60 MHz, in DaO + NaHCOs): ô 3.03 (s, N (CH3) 2), 3.58 (t, CH2), 4.70 (t, CH2)

Reference example 10

(1) While stirring a mixture of glycine-N, N-dimethylamide, triethylamine and methylene chloride, carbon disulfide and methyl iodide are added in this order. The mixture is stirred for 1 hour at room temperature and then shaken vigorously with 5% aqueous phosphoric acid solution. The organic layer is removed, washed with water, dried and evaporated to dryness under reduced pressure. The crystalline residue is stirred with n-hexane, filtered off and dried. This gives methyl 2- (N, N-dimethylcarbamoylmethyl) dithiocarbamate.

IR (KBr, cm-1): 1626.1543

NMR (60 MHz, in dö-DMSO) 8: 2.62 (s, CHsS), 3.02

(s, N (CH3) 2), 4.42 (d, J = 4Hz, CH2), 8.30 (br. s., NH)

(2) A mixture of methyl 2- (N, N-dimethylcarbamoyl-methyl) dithiocarbamate, sodium azide and ethanol is stirred at 80 ° G for 6.5 hours. The reaction mixture is adjusted to pH 2.5 with 10% hydrochloric acid and then evaporated to dryness under reduced pressure. The residue is extracted with 100 cc of methanol and the methanol extract is treated twice with activated carbon and dried. The powder remaining as a residue is recrystallized from water. This gives 1-N, N-dimethylcarbamoylmethyl-1H-tetrazole-5-thiol from the melting point 195 ° to 198 ° C. (dec.).

NMR (60 mHz, in dô-DMSO) 5: 2.87 & 3.07 (each singlet, N (CH3) 2), 5.21 (s, CH2CO)

(3) Using a sodium hydroxide solution, 1-N, N-dimethylcarbamoylmethyl-1H-tetrazole-5-thiol is hydrolyzed to give 1-carboxymethyl-1H-tetrazole-5-thiol having a melting point of 156 ° to 160 ° C. (dec.).

IR (ICBr, cm-1): 1713

NMR (60 MHz, in de-DMSO) 8: 5.03 (s, CH2CO), 12.09 (br. S, NH & -COOH)

Reference Example 11

38 g of sodium nitrite and 53 g of methyl acetoacetate are added to 200 cc of water. While cooling and stirring with ice, 200 cc of 4N sulfuric acid are added dropwise over a period of about 1 hour. During this dropwise addition, the temperature of the reaction mixture is kept at 5 ° to 8 ° C. The mixture is stirred within this temperature range for a further 2.5 hours and then extracted twice with 300 cc each of ethyl acetate. The extracts are poured together and washed twice with saturated aqueous sodium chloride solution. Then a solution of 96.7 g of sodium carbonate in 11 water is divided into three equal parts. This extracts 3-oxo-2-hydroxy-iminobutyrate from the above-mentioned ethyl acetate layer (three times). 200 ccm of methanol are added to the aqueous layer (11). After cooling with ice, 150 g of dimethyl sulfate are added dropwise with stirring within 10 minutes. After the addition, the mixture is stirred for 1.5 hours at room temperature and extracted twice with 300 cc of ethyl acetate. The extracts

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are poured together, washed with water and dried. The ethyl acetate is then distilled off and the residue is cooled with ice, whereby it solidifies. The solid residue is filtered off and washed with a small amount of water. 52.3 g of methyl 3-oxo-2-meth-oxyiminobutyrate are obtained in the form of white crystals with a melting point of 64.4 ° C.

Elemental analysis for C6H9NO4

Room temperature stirred. After addition of 500 ml of water, the reaction mixture is extracted twice with ethyl acetate. The extracts are poured together, washed with 5% aqueous sodium hydrogen carbonate solution and water in this order and dried. The solvent is then distilled off, 25 g of methyl 2-

(2-Chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetat in the form of crystals of melting point 130.8 ° C.

Calc .: C 45.28; Found: C 44.93;

5.70; 5.61;

N 8.80 N 8.71

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Elemental analysis: C9H11N3O4SCI

NMR spectrum (60 MHz, in CDCh): 2.40 ppm (3H, singlet,

Calculated: C 37.03; Found: C 37.30;

-Ç-CH3),

O

3.86 ppm) 3H, singlet, COOCH3), 4.10 ppm (3H, singlet, = NOCH3)

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Reference example 12

40 g of methyl 3-oxo-2-meth-oxyiminobutyrate are dissolved in 150 ml of chloroform. The solution is heated to 40 ° C. A solution of 40 g of bromine in 50 ml of chloroform is then added dropwise over the course of an hour. The reaction is then continued for one hour with stirring at room temperature. The reaction mixture is washed with 5% aqueous sodium hydrogen carbonate solution and water in this order. The organic layer is dried. The solvent is then distilled off to give 52.1 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate in the form of an oil.

NMR spectrum (60 MHz, in CDCb): 3.82 ppm (3H, singlet, 35 COOCH3), 4.09 ppm (3H, singlet, = N-OCH3), 4.27 ppm (2H, singlet, BrCH2CO)

52 g of methylr4-bromo-3-oxo-2-methoxyiminobutyrate are dissolved in 350 ml of tetrahydrofuran. To the solution are added 40 250 ml of water and then 89.1 g of sodium acetate trihydrate and 33.2 g of thiourea. The mixture is stirred at room temperature for 18 hours. 200 ml of a 5% aqueous sodium hydrogen carbonate solution are added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to remove the solvent. 200 ml of ether are added to the residue. The precipitate formed is filtered off. This gives 24.8 g of methyl 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate in the form of crystals of melting point 164.9 ° C.

Elemental analysis for C7H9N303S:

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H 3.45; H 3.40;

N N

14.40, 14.35

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Calc .: C 39.06; Found: C 38.78;

H 4.21; N H 4.15; N

19.52 19.33

NMR spectrum (60 MHz, in CDCb): 3.84 ppm (3H, singlet, COOCH3), 4.02 ppm (3H, singlet, = NOCH3), 5.74ppm (2H, 60 br. Singlet, NH2), 6.74ppm (lH, singlet, thiazole 5-H)

NMR spectrum (60 MHz, in CDCb): 3.90 ppm (3H, singlet, COOCH3), 4.02 ppm (3H, singlet, = NOCH3), 4.26 ppm (2H, singlet, CICH2CO), 7.24 ppm (lH, singlet, thiazole 5-H)

Reference Example 14 To a solution of 19.2 g of potassium hydroxide in a mixture of 170 ml of water and 900 ml of ethanol are added 20 g of methyl 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxy-iminoacetate. The solution is stirred for 2 hours at room temperature. The ethanol is distilled off under reduced pressure. After adding 170 ml of water, the residue is washed with 200 ml of ethyl acetate. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and extracted twice with 300 ml of ethyl acetate each time.

The extracts are poured together, washed with saturated aqueous sodium chloride solution and dried. The solvent is distilled off to obtain 16.8 g of 2- (2-chloro-racetamidothiazol-4-yl) -2- (syn) methoxyiminoacetic acid in the form of crystals. The NMR spectrum and the other properties show that this product is identical to the product prepared according to Reference Example 6.

Reference Example 15 1) 290 mg of 7-amino-3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid are dissolved in 6 ml of N, N-dimethylacetamide. While cooling with ice, 276 mg of 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxy-iminoacetyl chloride hydrochloride are added. The mixture is stirred for 15 minutes while cooling with ice and for 2 hours at room temperature. The reaction mixture is then diluted with 30 ml of water and extracted twice with 50 ml of ethyl acetate each time. The extracts are poured together, washed with 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off, 402 mg of 7- [2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -meth-oxyimino] -acetamido-3- (N-chloroacetyl) -carbamoyloxy-methyl-3- cephem-4-carboxylic acid can be obtained in the form of a viscous oil.

NMR spectrum (60 MHz, in CDCb): 3.50 ppm (2H, quartet, 2-CHî), 3.99 ppm (3H, singlet, NOCH3), 4.04.4.30 ppm (2Hx2, singletx2, CICH2COX2), 5.10ppm (lH, doublet, 6-H), 5.73ppm (lH, doublet, 7-H), 7.32ppm (lH, singlet, thiazole, 5-H)

Reference Example 13 21.5 g of methyl 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetate are dissolved in 90 ml of N, N-dimethylacetamide. While cooling with ice, 13.6 g of chloroacetyl chloride are added dropwise. The mixture is stirred for 30 minutes with ice and then for 30 minutes

2) The entire amount of the above product is dissolved in 9 ml of tetrahydrofuran. 6S 168 mg of thiourea and 300 mg of sodium acetate trihydrate are added to the solution. The mixture is stirred for 4 hours at room temperature. The precipitate is filtered off, washed with ether and dissolved in 5 ml of water. The solution is mixed with sodium

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bicarbonate is adjusted to a pH of about 7 and purified by column chromatography on the "Amberlite XAD-2" ion exchange resin. 58 mg of sodium 7- [2 (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-actamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylatin are obtained in the form of a white powder.

Elemental analysis for CisHisNéCbSîNa • 3HîO

Calc .: C 33.84; H 3.98; N, 15.78. Found: C, 33.94; H 3.82; N 15.42

NMR spectrum (60 MHz, in D2O): 3.47 ppm (2H, quartet, 2-CH2), 3.92 ppm (3H, singlet, = NOCH3), 4.68 ppm (2H,

quartet, -CH2OCONH2), 5.27 ppm (lH, doublet, 6-H), 5.72 ppm (1H, doublet, 7-H), 6.95 ppm (lH, singlet, thiazole 5-H)

Process for the preparation of 2- (2-chloroacetamido-thiazol-4-yl) -2- (syn) -methoxyiminoacetyl chloride

278 mg of the 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid prepared according to Reference Example 6 are suspended in 5 ml of methylene chloride. While cooling with ice, 208 mg of phosphorus pentachloride are added. The mixture is stirred at room temperature for 30 minutes and then washed with petroleum ether. This gives 276 mg of 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetyl chloride as a powder.

Elemental analysis for C8H7N3O3SCI2 • HCl

Calculated: C 28.89; Found: C 28.47;

H 2.42; H 2.73;

N 12.63 N 12.12

Reference Example 16

1) 762 mg of 7-aminocephalosporanic acid are dissolved in 15 ml of N, N-dimethylacetamide. While cooling with ice, 931 mg of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride (made from the syn isomer) are added. The mixture is stirred for 15 minutes while cooling with ice and for 2 hours at room temperature. The reaction mixture is diluted with 10 ml of water and extracted several times with 100 ml of ethyl acetate. The extracts are poured together, washed with 100 ml of saturated aqueous sodium chloride solution and dried. The ethyl acetate is distilled off, giving 1.4 g7- [2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -meth oxyiminoacetamido] cephalosporanic acid in the form of an oil.

2) The entire amount of the above product is dissolved in 30 ml of tetrahydrofuran, after which 500 mg of thiourea and then 895 mg of sodium acetate trihydrate are added. The mixture is stirred for 4 hours at room temperature. The precipitate formed is filtered off, washed with ether and dissolved in 6 ml of water. The solution is adjusted to a pH of about 7.0 with sodium hydrogen carbonate and purified by column chromatography on the "Amberlite XAD-2" ion exchange resin. This gives 78 mg of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] cephalosporanate as a white powder.

Elemental analysis for CieHiôNsCbSîNa • 2.5H20

Calc .: C Found: C

36.78; 36.93;

H 4.05; H 3.80;

N 13.40 N 12.68

ppm (1 H, doublet, 6-H), 5.81 (1 H, doublet, 7-H), 7.01 ppm (1 H, singlet, thiazole 5-H)

example 1

s To 10 ml of water are added 1 g of sodium sulfate 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] cephalosponate, prepared according to reference example 16.270 mg of 2-methyl-1 , 3,4-oxadiazole-5-thiol potassium salt and 7 mg of triethylbenzylammonium bromide. The mixture is stirred for 6 hours at 60 ° C under flowing nitrogen. After cooling, the reaction mixture is purified by column chromatography on the "Amberlite XAD-2" ion exchange resin. 110 mg of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- (2-methyl-15 l, 3,4-oxadiazol-5-yl ) thiomethyl-3-cephem-4-carboxylate in the form of a white powder.

Elemental analysis for C17H16N7O6S3 • 2h2o

Calc .: C 35.85; H 3.54; N 17.21 20 Found: C 35.73; H 3.72; N, 17.01

NMR spectrum (60 MHz, in D2O): 8.42 ppm (3H, singlet, oxadiazole 2-CH3), 3.55 ppm (2H, quartet, 2-CH2), 4.02 ppm (3H, singlet, = NOCH3), 5.13 ppm (lH, doublet, 6-H), 25 5.73 ppm (l H, doublet, 7-H), 6.97 ppm (lH, singlet, thiazole 5-H)

Example 2

Using sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] cephalosporanate and 30 heterocyclic thiol compounds in the manner described in Example 1, the following compounds are prepared:

a) Sodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxy-35 iminoacetamido] -3- (2-methyl-l, 3,4-thiadiazol-5-yl) - thio-

methyl 3-cephem-4-carboxylate

NMR spectrum (60 MHz, in D2O): 2.57 ppm (3H, singlet, thiazole 2-CH3), 3.52ppm (2H, quartet, 2-CH2), 3.95 ppm (3H, 40 singlet, = NOCH3), 5.18 ppm (lH, singlet, 6-H), 5.73 ppm (lH, singlet, 6-H), 5.73 ppm (lH, singlet, 7-H), 6.95 ppm ( lH, singlet, thiazole 5-H)

b) Dinatrim-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy- "4S iminoacetamido] -3- (2-carboxymethyl-l, 3,4-thiadiazol-5-

yl) thiomethyl-3-cephem-4-carboxylate

NMR spectrum (60 MHz, in D2O): 3.56 ppm (2H, quartet, 2-CH2), 3.96 ppm (3H, singlet, = NOCH3), 4.18 ppm (2H, so singlet, CmCQQNa) , 5.20 ppm (1 H, doublet, 6-H), 5.74 ppm (1 H, doublet, 7-H), 6.97 ppm (1 H, singlet, thiazole 5-H)

c) Sodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamido] -3- (l, 2,3-triazol-5-yl) thiomethyl-3-cephem -

55 4-carboxylate

NMR spectrum (60 MHz, in D2O): 3.57 ppm (2H, quartet, 2-CH2), 3.94 ppm (3H, singlet, = NOCH3; 5.21 ppm (lH, doublet, 6-H) , 5.72 ppm (lH, doublet, 7-H), 6.94 ppm (lH, singlet, 60 thiazole 5-H), 7.95 ppm (lH, singlet, triazol4-H)

d) Disodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamido] -3- (l-carboxymethyl-l, 2,3,4-tetrazol-5-yl ) -thiomethyl-3-cephem-4-carboxylate

65

NMR spectrum (60 MHz, in D2O): 2.07 ppm (3H, singlet, COCH3), 3.53 ppm (2H, quartet, 2-CH2), 3.98 ppm (3H, singlet, = NOCH3), 4.75 ppm (2H, quartet, 3-CH2), 5.21

NMR spectrum (60 MHz, in D2O): 3.55 ppm (2H, quartet, 2-CH2), 3.96ppm (3H, singlet, = NOCH3), 4.72ppm (2H, singlet,

15

630 635

-N-CHîCOONa),

5.18 ppm (lH, doublet, 6-H), 5.72 ppm (lH, doublet, 7-H), 6.95 ppm (lH, singlet, thiazole 5-H)

e) 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- [1 - (2-N, N-dimethylaminoethyl) -1,2,3,4 -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid betaine

NMR spectrum (60 MHz, in D2O): 3.01 ppm (6H, singlet,

CH3

CH3

3.50 ppm (2H, quartet, 2-CH2), 3.98 ppm (3H, singlet, = NOCH3), 5.18 ppm (lH, doublet, 6-H), 5.74ppm (lH, doublet, 7 -H), 6.96 ppm (1H, singlet, thiazole 5-H)

f) natrim-7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- (6-methyl-l-oxopyridazin-3-yl) thiomethyl-3- cephem-4-carboxylate

NMR spectrum (60 MHz, in D2O): 2.60 ppm (3H, singlet, pyridazine 6-CH3), 3.52 (2H, quartet, 2-CH2), 3.98 ppm (3H, singlet, = NOCH3 ), 5.21 ppm (lH, doublet, 6-H), 5.76 ppm (lH, doublet, 7-H), 6.95 ppm (lH, singlet, thiazole 5-H)

The minimum inhibitory concentration (jig / ml) of some of the compounds prepared in the manner described is given below.

Microorganism

connection

(a)

(e)

E. coli NIHJ

0.20

0.20

E. coli O-11

0.10

0.024

E. coli T-7

1.56

1.56

K. pneumoniae DT

0.05

0.10

K. pneumoniae GN 3835

0.39

0.20

Serr. marcescens IFO 12648

0.78

1.56

Serratia TN 0024

0.78

0.78

P. vulgaris IFO 3988

0.10

0.20

P. vulgaris GN 4413

1.56

1.56

P. mirabilis GN 4359

0.20

0.39

P. morganii IFO 3168

0.10

0.20

P. rettgeri 8 (TNO 336)

= 0.012

0.024

P. rettgeri GN 4733

0.39

0.78

Ent. cloacae IFO 12937

3.13

6.25

Cit. freundii GN 99

0.20

0.20

Cit. Freundii GN 1706

0.78

0.78

The abbreviations used to denote the microorganisms have the following meanings:

E: Escherichia, K: Klebsiella, Ps: Pseudomonas, Serr: Serratia, P: Proteus, Ent: Enterobacter, Cit: Citrobacter g) sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn ) methoxy-iminoacetamido] -3- (1-methyl-1 H-tetrazol-4-yl) thiomethyl-3-cephem-4-carboxylate

Elemental analysis for Ci6Hi6N905S3Na • 2h2o

Calc .: C 33.74; H 3.54; N 22.13 Found: C 34.18; H 3.57; N, 21.79

NMR spectrum (60 MHz, in D2O): 3.59 ppm (2H, quartet, 2-CH2), 3.93 ppm (3H, singlet, = NOCH3), 3.98 ppm (3H, singlet, N-CH3 ), 4.08 ppm (2H, quartet, 3-CH2), 5.12 ppm (1H, doublet, 6-H), 5.72 ppm (1H, doublet, 7-H), 6.93 ppm (1H , singlet, thiazole 5-H)

The minimum inhibitory concentrations (| ig / ml) of the compound g) described above are given below.

Microorganism

Compound g)

E. coli NIHJ

0.10

E. coli O-III

0.024

E. coli T-7

0.78

K. pneumonia DT

0.024

K. pneumonia GN 3835

0.20

Ps. Aeruginosa Pd 1

12.5

Ps. Aeruginosa PM 3

0.78

Ps. Aeruginosa P2

50

Ps. Aeruginosa GN3407

50

Serr. marcescens IFO 12648

0.78

Serratia TN 0024

0.20

P. vulgaris IFO 3988

0.024

P. vulgaris GN 4413

0.39

P. mirabilis GN 4359

0.10

P. morganii IFO 3168

0.05

P. rettgeri 8 (TN0336)

g 0.012

P. rettgeri 8 GN 4733

0.20

Ent. cloacae TN 1282

1.56

Cit. freundii GN 99

0.10

Cit. freundii GN1706

0.20

Acinetobacter anitratus TN-1140

25th

Example 3

1 g of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl is dissolved in 10 ml of dimethylformamide. 3-cephem-4-carboxylate dissolved. While cooling and stirring with ice, 0.85 g of iodomethyl pivalate is added. The mixture is stirred for 15 minutes. After adding 40 ml of ethyl acetate, the reaction mixture is washed with water, 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in this order and dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure and the residue is dissolved in a small amount of ethyl acetate and filtered. The filtrate is mixed with ether, after which it is cooled. The precipitate formed is filtered off. 0.4 g of piva-loyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (1-methyl-1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate obtained in the form of a white powder.

Elemental analysis for C22H27N9O7S3

Calculated: C 42.27; H 4.34 Found: C 42.29; H 4.40

Nuclear Magnetic Resonance Spectrum (60 MHz, in CDCb): 1.22 ppm (9H, singlet, -C (CH3) 3), 3.80 ppm (2H, broad singlet, 2-CH2), 3.94.4.06

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

630635

16

ppm (3Hx2, singletx2, N-CH3 & OCH3), 5.94 ppm (2H, singlet, -OCH2O), 5.12 ppm (lH, doublet, 6-H), 6.06 ppm (lH, doubletx2.7 -H), 4.44 ppm (2H, doublet, 3-CH2), 6.81 ppm (1H, singlet, thiazole 5-H).

Example 4

(1) In 20 ml of methylene chloride, 2.776 g of 2- (2-chloro-acetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid and 1.2 g of triethylamine are dissolved. 2.08 g of phosphorus pentachloride are added to the solution. The mixture is stirred at room temperature for 20 minutes and then 150 ml of hexane are added. The oily precipitate formed here is separated off and dissolved in 20 ml of tetrahydrofuran, a solution of 2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetyl chloride being formed. Separately, 3.143 g of 7-amino-3-acetylacetoxymethyl-3-cephem-4-carboxylic acid and 2.20 g of triethylamine are dissolved in 50 ml of 50% aqueous tetrahydrofuran. The acid chloride solution previously prepared is added dropwise to this solution while cooling with ice and stirring. The mixture is stirred for 2 hours while cooling with ice, after which water is added. The mixture is adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate is distilled off and ether is added to the residue. The crystalline product formed in this way is filtered off. 4.168 g of 7- [2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3-acetylacetoxy-methyl-3-cephem-4-carboxylic acid are obtained.

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-

acetamido] -3-acetylacetoxymethyl-3-cephem-4-carboxylate.

In 10 ml of water, 933 mg of the above-mentioned product, 350 mg of l- (2-N, N-dimethylaminoethyl) -lH-tetrazole-5-thiol and 168 mg of sodium hydrogen carbonate are dissolved. The mixture is stirred at 55 ° C for 1 hour. The reaction mixture is then passed directly through a column filled with the ion exchange resin «Amberlite XAD-2» 10 for purification. 170 mg of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [l- (2-N, N-dimethylaminoethyl) -lH-tetrazol-5 -yl] thiomethyl-3-cephem-4-carboxylate in the form of a white powder. In the NMR spectrum and in the other properties, this product is identical to the product obtained according to Example 2.

The following table illustrates the protective effect (ED50 *, mg / kg) of the compounds prepared according to the example above on infected mice.

20th

25th

30th

Connection according to the example

administration

EDso *

(mg / kg)

2 (9)

subcutaneous

0.022

(CER: 1.25)

3rd

orally

0.11

(CEX: 2.51)

4th

orally

0.27

(CEX: 2.51)

* Test animals: male mice (ICR / SLC)

5 mice per group per single dose of infection: intraperitoneally with E. coli O-111

NMR spectrum (60 MHz, in de-DMSO): 2.14ppm (3H, singlet,

-C-CH3),

O

3.60 ppm (4H, broad, singlet,

-C-CH2-C- &

II. II

O O

Observation time: 7 days (); Control SC - subcutaneous 35 CER = cephaloridin ol

40

ch2c0nh +

, ^ lN ^ -ch2N (JÎ

0

CÜÜ

2-CH2), 3.86 ppm (3H, singlet, OCH3) 4.34ppm (2H, singlet, CICH2CO), 4.91 ppm (2H, quartet, 3-CH2), 5.13 ppm (lH, doublet, 6-H), 5.80 ppm (lH, doubletx2.7-H), 7.40 ppm (lH, singlet, thiazole 5-H)

(2) 4.00 g of the 7- [2- (2-chloroacetamidothiazol-4-yl) -2- (syn) -rnethoxyiminoacetamido] -3-acetylacetoxymethyl-3-cephem- are prepared in 20 ml of dimethylacetamide. 4-carboxylic acid dissolved. 1.06 g of thiourea are added to the solution. The mixture is stirred at room temperature for 17 hours and then 100 ml of ether are added. The oily precipitate is separated off and dissolved in 5% aqueous sodium hydrogen carbonate solution. The solution is freeze-dried and the powder product obtained is added to 50 ml of methanol. The insoluble matters are filtered off and the filtrate is added to 300 ml of ether. The precipitate is filtered off. Here, 3.150 g

45

CEX = cephalexin

»Qihc0 jt's ^

NH2 G

• n

-ch,

cooh

55

The structures and key figures (IR spectrum) of the compounds prepared according to the above-described processes according to the invention (No. 1 to) are listed in the table below. In this table, the IR-60 spectrum (cm-1, KBr) means the characteristic absorption band attributable to the β-lactam component.

17th

630 635

r2nh g y Ì s

■ fj il n_r1 ™ 0.00 °

n c-conh n

n 0

coom

Compound No. R2 Rj M IR

(cm-1, KBr)

N - N

-SAJ Na 1760

N - N

H Na 1763

H

N - N

Na 1758

ch,

H-bXJ Na 1760

CH3

H ïï rf CH3 Na 1763

-Bn

S "CF3

H N - N Na 1765

-s-KQß-m2

ïï - N -s NHCOOCH-

630 635

18th

Compound No. R2 R3 M IR

(cm "1, KBr)

N - N

H -sAßJ ^ CHgCOHHg Na 1765

N - N

H Na 1768

CH2C0NH2

10 h

N - N

-s-llnj-eh2 Na 1768

ch3

11 H -OH Na 1760

12 h

N - N CH

-bAqJLcH2N <5 Na 1765

S CHj

N - N

13 H -S-4gJi-SGH2COONa Na

N - N

H

15 H rb

CHgSO ^ Na

N

1768

14 H 1 Na 1765

CHgCOONa

N - N

-sA „i Na 1765

CHs n— ^ I

16 H -s - * l Jj -CH2OCOC-CH3 1765

to N I

■ H CHs

19th

630 635

Connection No. R2 Rì IR

(cm "1, KBr)

n - n

Il II CH3

-S-V-N 1

17 H i CH, -CH2OCOC-CH3 1768

CH0CH0N <5 1

• 2 2 CH CH3

n - n

18 H J ïï -CHOCOOC2H5 1765

I.

1 CHs ch3

Il? -CHOCOOC2H5 1768 19 H-S-U Jf I

CH3

H

CHs n - n '

20 il II -CHOCOC-CHs 1765

: -s-lrn! i

CH2CH2N <5

CH, CH3 CH3

ch,

21 H \ AJ ™

CH5

II

0

«-« y v ~

23 H N çjj “1768

CHoCHoNC 5 0 2 ^ CH ^

B

Claims (15)

630 635 PATENT CLAIMS 1. Process for the preparation of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyirainoacetamido] cephalosporin derivatives of the formula: r2nh- a N U- C. -conh och. (v) CH2R5 wherein R5 is a hydroxyl or mercapto group or a heterocycle bonded via a sulfur atom and R2NH is an optionally protected amino group, and 15 their pharmaceutically acceptable salts, characterized in that a compound of the formula: r2nh (iv) wherein R2NH has the meaning given above and R4 represents acyloxy, carbamoyloxy or halogen, with a compound of the formula HRs. 2. The method according to claim 1, characterized in that compounds of the above formula are prepared in which R2 is a monohaloacetyl group. 3. The method according to claim 1, characterized in that a compound obtained, in which R2NH represents a protected amino group, is converted into the corresponding free amino compound by splitting off the protective group. 4. The method according to claim 1 or 3, characterized in that compounds of the above formula are prepared in which the heterocycle bonded via a sulfur atom R5 is unsubstituted or substituted. 5. The method according to claim 4, characterized in that the heterocyclic group is a 5- or 6-membered group with 1 to 4 heteroatoms from the group consisting of oxygen, sulfur and nitrogen atoms, the nitrogen atom or nitrogen atoms in oxide form can be present. 6. Process according to claims 4 and 5, characterized in that pyridyl, N-oxopyridyl, pyrimidyl, pyridazinyl, N-oxopyridazinyl, pyrazoleyl, diazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl or tetrazolyl are contained as heterocyclic group. 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (l-sulfomethyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and their pharmaceutically acceptable salts. 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (6-methyl-l-oxopyridazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid and their pharmaceutically acceptable salts, and 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- [l- (2-N, N-dimethylaminoethyl) -l, 2,3,4-tetrazole -5-yl] -thiomethyl-3-cephem-4-carboxylic acid and its pharmaceutically acceptable salts, 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carbon -65 acid and its pharmaceutically acceptable salts, 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (l-carboxymethyl-l, 2,3,4- tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid and its pharmaceutically un 630 635 conceivable salts, 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-60 amido] -3- (2-carboxymethyl-1,3,4-thiadiazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid and its pharmaceutically acceptable salts, 7- [2- (2- (Aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- 50 carboxylic acid and its pharmaceutically acceptable salts, 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (2-methyl-l, 3,4-oxadiazol-5 -yl) thiomethyl-3-cephem-4-carboxylic acid and its pharmaceutically acceptable salts, 55 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacet-amido] -3- (2-methyl-l, 3,4-thiadiazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid and its pharmaceutically acceptable salts, 7. The method according to claim 6, characterized in that the thiadiazolyl group is 1,2,3-thiadiazolyl, 1,2,4-thia-diazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl, the oxadiazolyl group 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl, the triazolyl group is 1,2,3-triazolyl or 1,2,4- Triazolyl and the tetra-zolyl group is 1 H-tetrazolyl or 2H-tetrazolyl. 8. The method according to claim 6, characterized in that the heterocyclic group 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 H-tetrazolyl , Imidazolyl or thiazolyl. 9. The method according to claim 4, characterized in that the heterocyclic group by one or two radicals from the lower alkyl, lower alkoxy, halogen, tri- CHjRjj halogen-lower alkyl, hydroxyl, mercapto, amino, Car-3 »boxyl, carbamoyl, diniederalkyl-amino-substituted lower alkyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino existing group is substituted. 10th 10. The method according to claim 4, characterized in that the heterocyclic group by one or two radicals from the lower alkyl, lower alkoxy, halogen, tri-halogeno-lower alkyl, hydroxyl, mercapto, amino, car-boxyl, carbamoyl, di-lower alkyl -amino substituted lower alkyl and caboxymethyl group is substituted. 11. The method according to claim 1 or 3, characterized in that compounds of the above formula are prepared in which R5 (l-methyl-lH-tetrazol-5-yl) thio or (2-methyl-l, 3,4-thiadiazole -5-yl) thio. 45 12. The method according to claim 1 or 3, characterized in that the following compounds are produced: 13. The method according to claim 1 or 3, characterized in that the carboxylic acid obtained is converted into a corresponding salt by reaction with a pharmaceutically acceptable base. 14. A process for the preparation of esters of 7- [2- (2-ami-nothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] cephalo-sporine derivatives of the formula I shown in claim 1, characterized in that after the process according to claim 1 produces a carboxylic acid of said formula I and esterifies this carboxylic acid. 15. The method according to claim 14, characterized in that pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (l-methyl-lH-tetrazole-5 -yl) -thiomethyl-3-cephem-4-carboxylate. 15